The present invention relates to a new process for preparing certain known cycloalkylidenemethylphenylacetic acid derivatives which have valuable anti-inflammatory activities.
The cycloalkylidenemethylphenylacetic acid derivatives to which the present invention relates are described and claimed, inter alia, in U.S. Pat. No. 4,254,274 and may be represented by the formula (I): ##STR4## in which R.sup.1 represents a hydrogen atom or a C.sub.1 -C.sub.4 alkyl group and n is 1, 2 or 3. The preparation of such compounds is described and claimed in U.S. Pat. No. 4,365,076.
In the prior patent, the compounds are prepared by reacting a benzaldehyde carboxylic acid ester of formula (IIa): ##STR5## (in which R.sup.1 is as defined above and R.sup.a represents a C.sub.1 -C.sub.3 alkyl group) with an enamine derivative of formula (III): ##STR6## (in which n is as defined above and R.sup.2 and R.sup.3 are the same or different and each represents a C.sub.1 -C.sub.6 alkyl group or they jointly form, together with the nitrogen atom to which they are attached, a cyclic amino group optionally having a ring oxygen atom). The product of the reaction of compounds (IIa) and (III), an intermediate which is not normally isolated, is then hydrolized to give an ester of the compound of formula (I); this ester may then be hydrolized to convert it to the acid, either as a separate step or, by carrying out the reaction between the compounds (IIa) and (III) in the presence of a suitable base, as part of the same step as that reaction.
Although this prior process works well, it is not totally satisfactory and there are certain elements involved in the process which could be improved in order to give a process which functions even more effectively on a commercial scale. Specifically:
(a) Thus, the aldehyde ester of formula (IIa) is normally prepared as a mixture comprising a major proportion of the desired para isomer and a minor proportion of the undesired ortho and meta isomers, these isomers all being oily compounds. As a result, a specific extra purification step is required to separate this mixture and obtain just the desired para isomer. It is possible to use the mixture of isomers of the esters (IIa) in the above reaction, to produce a mixture comprising the compound of formula (I) and the corresponding meta and ortho isomers, but these isomers still must be separated, which requires a specific purification step as they are all crystalline compounds.
(b) In the prior process, the most satisfactory solvents to use (from the point of view of ensuring a smooth reaction) are aromatic hydrocarbons, in particular benzene, which was successfully used in Examples 1 and 2 of U.S. Pat. No. 4,254,274 and No. 4,365,076. Benzene, however, is not the most desirable of solvents for use on an industrial scale as it pollutes the environment and has a deleterious effect on workers' health. Accordingly, when benzene is used on an industrial scale, measures are normally taken to protect the environment and the workers: these have an effect on the economy of the process. Other solvents which can be used are toluene and xylene; however, where these are used, in practice it is necessary to carry out the reaction at reflux temperature, and, even then, the reaction takes a long time. This adversely affects the economy of the process. None of these problems is unsuperable and, indeed, other factors may make it desirable to employ a solvent despite disadvantages of the type described above. However, it would clearly be desirable to provide a process for preparing compounds of formula (I) which can be operated more successfully in a wider range of solvents so as to provide the facility, if desired, of using a solvent free from these disadvantages or possessing them to a lesser degree.
(c) The final step of the above process comprises hydrolizing the ester to give the free acid of formula (I). However, under the conditions required for this hydrolysis, cleavage of the enone carbon-carbon bond tends to occur, because of a retro-aldol reaction, which not only reduces substantially the yield of the desired product, but also increases the difficulty of purification of that product.
(d) As noted above, the final product will normally contain some of its ortho and meta isomers and will require purification to remove these. It would be desirable to provide a process which does not produce a final product containing these isomers and where, hence, purification can be simplified. For example, the most effective means of purifying the products of the prior process is by means of high vacuum distillation. It is an important and unexpected advantage of the present invention that simpler purification procedures can be used, if desired.
In conclusion, the prior process of U.S. Pat. No. 4,254,274 and No. 4,365,076 has certain disadvantages, some of which lead to relatively low yields. Thus, the yield of the reaction in Example 1 of U.S. Pat. No. 4,254,274 and No. 4,365,075--the production of ethyl 2-[4-(2-oxo-1-cyclohexylidenemethyl)phenyl]propionate--was about 32%. The yield of Example 4 of said U.S. Patent--the hydrolysis of this ethyl ester to 2-[4-(2-oxo-1-cyclohexylidenemethyl)phenyl]propionic acid--was 51%. However, the overall yield of the process consisting of Example 1 followed by Example 4 was merely 16.3%, which is undesirably low for a commercial process.
Whilst each of the disadvantages of the prior process is relatively minor, together they can have a significant effect on the economy, and hence profitability and viability, of the process.
We have now discovered how these disadvantages may be overcome in a simple, yet unexpected, way.